β-carboline derivatives and its pharmaceutical use against depression and anxiety

ABSTRACT

The invention provides compounds of formula (I) wherein R1 to R5 are as defined in the description, and their preparation. The compounds of formula (I) are useful as pharmaceuticals.

The present invention relates to novel β-carboline derivatives, theirpreparation, their use as pharmaceuticals and pharmaceuticalcompositions containing them.

More particularly the invention provides a compound of formula I

wherein

-   R₁ is a group of formula-    wherein R₆ is (C₁₋₄)alkyl, R₇ and R₈, independently, are hydrogen    or (C₁₋₄)alkyl and X is hydrogen, (C₁₋₄)alkoxy, (C₁₋₄)alkylamino or    di(C₁₋₄)alkylamino,-   R₂ and R₃, independently, are (C₁₋₄)alkoxy(C₁₋₄)alkyl or    (C₃₋₇₋)cycloalkyl(C₁₋₄)alkyl, or, provided R₁ is not an optionally    substituted phenyl group, (C₁₋₁₂)alkyl,-   R₄ is hydrogen, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen or    trifluoromethyl and-   R₅ is hydrogen or (C₁₋₄)alkyl,    in free base or acid addition salt form.

On account of the asymmetrical carbon atom(s) which is (are) present inthe compounds of formula I and their salts, the compounds may appear inoptically active form or in form of mixtures of optical isomers, e.g. inform of racemic mixtures. All optical isomers and their mixturesincluding the racemic mixtures are part of the present invention.

The compounds of formula I and their salts may also appear in thetautomeric forms having the formulae Ia and Ib

Both tautomatic forms are part of the present invention.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine orchlorine. The above-defined alkyl and alkoxy groups preferably representmethyl and methoxy.

In a further aspect, the invention provides a process for the productionof the compounds of formula I and their salts, whereby a compound offormula II

wherein R₁, R₄ and R₅ are as defined above, is reacted with a compoundof formula III

wherein R₂ and R₃ are as defined above, and the compounds of formula Ithus obtained are recovered in free base or acid addition salt form.

The reaction can be effected according to known methods, e.g. asdescribed in Example 1.

Working up the reaction mixtures according to the above process andpurification of the compounds thus obtained may be carried out inaccordance to known procedures.

Acid addition salts may be produced from the free bases In known mannerand vice-versa.

The compounds of formula II and III are known or may be preparedaccording to known procedures, for example according to WO 99/64420 forthe compounds of formula II.

Compounds of formula I and their pharmaceutically acceptable acidaddition salts, hereinafter referred to as agents of the Invention,exhibit valuable pharmacological properties when tested in vitro usingsomatostatin (somatotropin release inhibiting factor, SRIF) receptorexpressing cell cultures and in animals, and are therefore useful aspharmaceuticals.

In particular the agents of the invention show high affinity tosomatostatin receptors. More particularly they are selective antagonistsat somatostatin sst₃ receptors, previously called SSTR-3 receptors (seeHoyer et al., TiPS, 1995, 16; 86-88), as determined in radioligandbinding and second messenger studies [see for example K. Kaupmann etal., FEBS Letts. 1993, 331:53-59. S. Siehier et al. NaunynSchmiedeberg's Arch Pharmacol, 1999, 360: 488-499] where they exhibitselective affinity for sst₃ receptors with pKd values between about 7.5and 9.0 and act as antagonists with pKi values of about 7.5 to 9.0 (S.Siehler & D. Hoyer, Naunyn Schmiedeberg's Arch Pharmacol, 1999: 360:510-521).

The agents of the invention are therefore useful for treatment inanxiety, depression, social phobia, panic disorders, GAD (generalizedanxiety disorders), OCD (obsessive compulsive disorders), post traumaticstress disorders, somatoform disorders, personality disorders, ADHD(attention deficit and hyperactivity disorders), bipolar disorders,schizophrenia, including negative symptoms, neurodegenerative diseasessuch as leaming/mlmory disorders, dementia, age associated memoryimpairment, senile dementia of Alzheimer's type (SDAT), for thetreatment of tumours and for vascular disorders and immunologicaldiseases, as confirmed in a range of standard tests as indicated below.

In the social exploration test at doses of about 0.01 to 10 mg/kg p.o.,the agents of the invention increase social contact time of ratssimilarly to classical anxiolytics such as benzodiazepines e.g.chlordiazepoxide or NK1 antagonists (Vassout A, Veenstra S, Hauser K,Ofner S, Brugger F, Schilling W, Gentsch C, Regulatory Peptides. 2000;96, 7-16).

Furthermore in the mouse intruder test [Triangle, 1982, 21: 95-105; J.Clin. Psychiatry, 1994, 55:9 (suppl. B) 4-7], the agents of theinvention increase social investigation and reduce defensive ambivalencein the treated intruder mouse at doses of about 1 to about 10 mg/kgs.c., suggesting an antimanic profile similar to carbamazepine andlithium, a neuroleptic profile like clozapine and an anxiolytic profilelike diazepam.

In the stress-induced hyperthermia- and the elevated plus-maze paradigmin mice [Lecci et al., Psychopharmacology 101:255-261 (1990) and RodgersR. J. Behav. Pharmacol. 8: 477-496 (1998), respectively] the agents ofthe invention reduced the increase in body-temperature and increased thetime spent on the open arms, respectively. They are therefore indicatedfor the treatment of anxiety disorders and panic disorders.

However, in contrast to benzodiazepines, the compounds of the inventiondo not impair memory as measured in the passive avoidance test, aparadigm in which memory formation impairment e.g. by benzodiazepines,glutamate NMDA receptor antagonists or muscarinic antagonists (VenableN; Kelly PH, Psychopharmacology; 1990: 100, 215-21) have been detected.

At doses of about 0.3 to 3 mg/kg p.o., the agents of the inventionincrease exploratory behaviour of mice in the open half of the halfenclosed platform, a model which is predictable for anxiolytic activity(Psychopharmacology, 1986, 89:31-37). In the same half enclosed platformmodel, the agents of the invention, at the doses indicated above, alsoincrease vigilance of the mice.

The compounds are therefore indicated for the treatment of depression,schizophrenia and dementia, in particular of senile dementia of theAlzheimer type (SDAT).

The agents of the invention at 0.03-3 mg/kg p.o. enhance leaming/mlmoryin mice as measured in the social recognition test similar to oxiracetamor GABA_(B) blockers (Thor D. H. and Holloway W. R. J. Comp. Physiol.Psychol. 1982; 96: 1000-1006. Mondadori C. et al., Behavioural BrainResearch 1996, 77: 227-229). Further, the agents at 0.03-0.3 mg/kg p.o.significantly Increased both recognition and discrimination indices inrats in a non-social situation using the object recognition test (ORT,Ennaceur A and Delacour J. Behav Brain Res 1988; 31: 47-59), similar torivastigmine (Exelon®).

The compounds are therefore indicated for the treatment of cognitivedisturbances and leaming/mlmory disorders.

The positive effects on memory acquisition/retention combined with thesoclotropic components displayed by the agents of the invention, suggestthat these will prove useful in the treatment of ADHD and various typesof dementias, including Alzheimers disease.

Furthermore at said acute doses the agents of the invention increaseaggressive behaviour (attacks, chases, bites) in the Matched PairsSituation test in mice [Dixon et al., J. Clin. Psychiatry 1994: 55: (9)[Suppl. B] 4-7]. Since as mentioned above they additionally attenuatedefensive behaviours in the intruder mouse test, the agents of theinvention exhibit an ethopharmacological profile which is very similarto that of clozapine and to some extent to that of antimanic agents(lithium, carbamazepine, valproate). They are therefore indicated forthe treatment of affective disorders including bipolar disorders e.g.manic-depressive psychoses, extreme psychotic states e.g. mania,schizophrenia, and excessive mood swings where behavioural stabilisationis desired. In addition, the compounds are indicated in anxiety states,generalised anxiety as well as social stress and agoraphobia, as well asthose behavioural states characterised by social withdrawal e.g.negative symptoms [Dixon A. K. Brit. J. Med. Psychol. 71: 417-445; DixonA. K., Fisch H. U. Neuroscience and Biobehavioural Reviews. 1990: 23;345-358] and post traumatic stress disorders.

The agents of the invention show antidepressant-like effects in the rat,similar to desipramine or fluoxetine when given subchronically (10-30mg/kg, p.o.) in the forced swim test. (Porsolt, R. D. et al. Nature.1977: 266, 730-732) and also produce antidepressant-like effects in themouse, similar to fluoxetine (Porsolt, R. D. et al. Nature 1977: 266,730-732). Finally, these agents, when given once per day for 14 days,(0.3-30 mg/kg p.o.), reverse both the characteristic hyper-reactivity ofbulbectomised rats when first placed in a novel and stressfulenvironment and the total activity, similar to imipramine anddesipramine. (Song C and Leonard BE. Hum. Psychopharmacol 1994; 9:135-146).

Collectively, this set of data suggests strong antidepressant potentialfor the agents of the invention. Combined with the aforementionedeffects, the agents of the invention are indicated for uni-and bipolardepressive disorders, generalised anxiety disorders, post traumaticstress disorders, social phobia and anxiety, panic attacks, aggression,pre-menstrual dysphoria and autism, ADHD (attention deficit andhyperactivity disorders), schizophrenia, including negative symptoms,neurodegenerative diseases such as leaming/mlmory disorders, dementiasassociated with various neurological disorders, age-associated memoryimpairment, and SDAT.

The agents of the invention are also effective In the treatment ofvarious kinds of tumours, particularly of sst₃ receptor bearing tumours,as indicated in proliferaton tests with various different cancer celllines and in tumour growth experiments in nude mice with hormonedependent tumours [see for example: G. Weckbecker et al., CancerResearch 1994, 54: 6334-6337]. Thus, the compounds are indicated In thetreatment of, for example, cancers of the breast, the prostate, thecolon, the pancreas, the brain and the lung (small cell lung cancer) andfor In vivo imaging of sst₃ receptor bearing tumours.

For all the above mentioned indications, the appropriate dosage will ofcourse vary depending upon, for example, the compound employed, thehost, the mode of administration and the nature and severity of thecondition being treated. However, In general, satisfactory results Inanimals are indicated to be obtained at a daily dosage of from about 0.1to about 10 mg/kg animal body weight. In larger mammals, for examplehumans, an indicated daily dosage is in the range from about 5 to about200 mg, preferably about 10 to about 100 mg of the compound convenientlyadministered in divided doses up to 4 times a day or in sustainedrelease form.

The agents of the invention may be administered in free form or inpharmaceutically acceptable salt form. Such salts may be prepared inconventional manner and exhibit the same order of activity as the freecompounds.

Accordingly in a further aspect the present invention provides theagents of the invention for use as pharmaceuticals, more specificallyfor treatment in the above-mentioned conditions, e.g. schizophrenia,depression, anxiety and bipolar disorders.

The present invention furthermore provides a pharmaceutical compositioncomprising an agent of the invention in association with at least onepharmaceutically acceptable diluent or carrier. Such compositions may beformulated In conventional manner. Unit dosage forms contain, forexample, from about 0.25 to about 50 mg of an agent according to theinvention.

Agents of the invention may be administered by any conventional route,for example parenterally e.g. in form of injectable solutions orsuspensions, or enterally, preferably orally, e.g. in the form oftablets or capsules.

The agents of the invention may alternatively be administered e.g.topically in the form of a cream, gel or the like, or by inhalation,e.g. in dry powder form.

Examples for compositions comprising an agent of the Invention include,e.g. a solid dispersion, an aqueous solution, e.g. containing asolubilising agent, a microemulsion and a suspension of an agent of theinvention. The composition may be buffered to a pH in the range of e.g.from 3.5 to 9.5, by a suitable buffer.

The agents of the invention can be administered either alone or incombination with other pharmaceutical agents effective in the treatmentof conditions mentioned above.

Thus, the agents of the invention can be used for the treatment ofdepressive symptoms in combination with: tricyclics, MAO inhibitors,SSRI's, SNRI's, NK receptor antagonists, CRF-receptor antagonists, 5HT₇receptor-antagonists, mGlu receptor agonists/antagonist/modulators,GABA-_(A) or GABA-_(A/B) receptor agonist/antagonists or modulators,vasopressin receptor antagonists, electroconvulsive shock, sleepdeprivation, or herbal medicine such as St. John's Worth.

The agents of the invention can also be used for the treatment ofanxiety-symptoms in combination with: benzodiazepines includingmitochondrial benzodiazepine-ligands, 5-HT_(1A) receptor agonists,SSRI's, SNRI's, NIK receptor-antagonists, CRF receptor-antagonists,vasopressin receptor-antagonists, mGlu receptoragonists/antagonist/modulators, GABA-_(A) or GABA-_(A/B) receptoragonists-antagonists or modulators.

The agents of the invention can further be used for the treatment of anyforms of dementia, including Alzheimer's disease (SDAT) in combinationwith: acetylcholine-esterase inhibitors, such as rivastigmine anddonepezil, mixed acetylcholine/butyrylcholine esterase-inhibitors andnicotinic-alpha₇-receptor agonists.

Moreover the agents of the invention can be used for the treatment ofpsychotic symptoms, including positive and negative symptoms inschizophrenia and schizoid type syndromes in combination with: anytypical or a typical antipsychotic, such as clozapine or haloperidol,and nicotinic-alpha₇-receptor agonists.

Furthermore the agents of the invention can be used for the treatment ofbipolar disorders in combination with: any antimanic agent (e.g.Lithium, Carbamazepine, Valproate) or any a typical or typicalantipsychotic.

The pharmaceutical compositions for separate administration of thecombination partners and for the administration in a fixed combination,i.e. a single galenical composition comprising at least two combinationpartners according to the invention, can be prepared in a manner knownper se and are thus suitable for enteral, such as oral or rectal, andparenteral administration to mammals, including man, comprising atherapeutically effective amount of at least one pharmacologicallyactive combination partner alone or in combination with one or morepharmaceutically acceptable carriers, especially suitable for enteral orparenteral application.

In particular, a therapeutically effective amount of each of thecombination partners may be administered simultaneously or sequentiallyand in any order, and the components may be administered separately oras fixed combination.

Accordingly the invention also provides a combination comprising atherapeutically effective amount of an agent of the invention and asecond drug substance, said second drug substance being for example foruse in any of the particular indications hereinbefore set forth.

The preferred indications are schizophrenia (especially negativesymptoms and cognitive impairment), depression, anxiety and affectivedisorders, including bipolar disorders, e.g. mania.

The preferred agent of the invention for the above-mentioned indicationsis the(R)-1,1-bis-ethoxymethyl-3-(4-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline,in free base or acid addition salt form. This compound shows strongaffinity for sst₃ receptors (human receptor: pKd=8.69; mouse receptor:pKd=8.30) with a selectivity of more than 400 fold over othersomatostatin receptors. In the social contact assay (rat), it increasesdose dependently the duration of social contacts of the “intruder”towards the “resident” at 0.01-10 mg/kg p.o. (maximal amplitude at 0.3-3mg/kg p.o.), similarly to a single dose of chlordiazepoxide of 5 mg/kgp.o. In the passive avoidance test at 0.1, 1 or 10 mg/kg p.o., incontrast to chlordiazepoxide at 20 mg/kg p.o., no impairment of memoryformation is observed. In the social recognition test (mice), at dosesbetween 0.03 and 3 mg/kg p.o., the compound produces a significantincrease of social recognition of a familiar partner, which isindicative of enhancement of leaming/mlmory. In the forced swim test(Porsolt), the immobility time is shortened by 30-45% on subchronicadministration of 12.5-25 mg/kg p.o.

In accordance with the foregoing, the present invention also providesthe use of an agent of the invention as a pharmaceutical, e.g. for thetreatment of schizophrenia, depression, anxiety and bipolar disorders.

Moreover the present invention provides the use of an agent of theinvention for the manufacture of a medicament for the treatment of anycondition mentioned above, e.g. schizophrenia, depression, anxiety andaffective disorders.

In still a further aspect the present invention provides a method forthe treatment of any condition mentioned above, e.g. schizophrenia,depression, anxiety and bipolar disorders, in a subject in need of suchtreatment, which comprises administering to such subject atherapeutically effective amount of an agent of the invention.

The following examples illustrate the invention. The temperatures aregiven in degrees Celsius and are uncorrected.

EXAMPLE 1(R)-1,1-Dibutyl-3-(4-pyridin-4-yl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline

1. 2-Bromo-1-pyridin-4-yl-ethanone Hydrobromide

2-Bromo-1-pyridin-4-yl-ethanone hydrobromide is prepared from1-pyridin-4-yl-ethanone in 83% yield according to a known procedure (A.Taurins, A. Blaga, J. Heterocycl. Chem. 7, 1139 (1970)).

2.[(R)-2-(1H-indol-3-yl)-1-(4-pyridin-4-yl-1H-imidazol-2-yl)-ethyl]-carbamicAcid Tert Butyl Ester

A solution of Boc-D-tryptophan (7.00 g, 23.0 mmol) and Cs₂CO₃ (7.49 g,23.0 mmol) in DMF (85 ml) is stirred for 30 min at room temperature.2-Bromo-1-pyridin-4-yl-ethanone hydrobromide (6.49 g, 23.0 mmol) isadded and stirring is continued at room temperature for 1 h. The solventis removed in vacuo, the residue Is resuspended in AcOEt, filtered overhyflo and evaporated. The resulting oil is taken up in xylene (290 ml),ammonium acetate (35.46 g, 460 mmol) is added and the mixture is heatedfor 2 h at 160° using a Dean-Stark trap. After cooling to roomtemperature, AcOEt (100 ml) is added and the solution is washed withsat. aq. K₂CO₃ solution and brine (100 ml each). The aqueous layers arereextracted with AcOEt (2×100 ml); the combined organic layers are driedover Na₂SO₄ and evaporated. MPLC (400 g silica gel, AcOEt:MeOH 95:5 to90:10) yields 3.36 g (36%) of [(R)-2-(1H-iundol-3-yl)-1-(4-pyridin-4-yl-1H-imidazol-2-yl)-ethyl]-carbamic acidtert-butyl ester (TLC: silica gel, toluene:ethanol 5:1, R_(f)=0.31).

3. (R)-2-(1H-indol-3-yl)-1-(4-pyridin-4-yl-1H-imidazol-2-yl)-ethylaminedihydrochloride

[(R)-2-(1H-indol-3-yl)-1-(4-pyridin-4-yl-1H-imidazol-2-yl)-ethyl]-carbamicacid tert-butyl ester (3.46 g, 8.58 mmol) is dissolved in a mixture ofglacial acetic acid (99.5%, 25 ml) and conc. aq. HCl (37%, 2.5 ml) andthe solution is stirred under argon at room temperature for 1 h. Theresulting precipitate is filtered, washed with acetone and dried to give3.04 g (94%) of(R)-2-(1H-indol-3-yl)-1-(4-pyridin-4-yl-1H-imidazol-2-yl)-ethylaminedihydrochloride (TLC: silica gel, toluene:ethanol:AcOH 4:4:1,R_(f)=0.18).

4.(R)-1,1-Dibutyl-3-(4-pyridin-4-yl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1βl-carboline

A mixture of the above amine dihydrochloride (1.200 g, 3.19 mmol) and5-nonanone (0.544 g, 0.663 ml, 3.83 mmol) in n-butanol (20 ml) isrefluxed at 135° for 4.5 h. Using a Dean-Strark trap, 2 ml of thesolvent are distilled off, then stirring is continued at 135° for 2 hand at 100° for 15 h. After cooling to room temperature and evaporationof the solvent, AcOET (50 ml) is added and the solution is washed withsat. aq. NaHCO₃ solution (20 ml), the aqueous layer is reextracted withAcOEt (2×50 ml), the combined organic layers are dried over Na₂SO₄,filtered and evaporated. After MPLC (80 g silica gel, AcOEt:triethylamine 95:5) and recrystallization from methanol:water (80:20)(R)-1,1-Dibutyl-3-(4-pyridin-4-yl-1H-imidazol2-yl)-2,3,4,9-tetra-hydro-1H-β-carboline (0.806 g, 59%) is obtained as acolourless crystalline solid (mp. 200-205°, TLC: silica gel,toluene:ethanol 5:1, R_(f)=0.42, ESI-MS: [M+H]⁺=428.2).

The following compounds of formula I wherein R₄ and R₅ are hydrogen canbe prepared in analogy to Example 1.

Example R1 R2 R3 mp. (base) [M + H]⁺ 2 Pyridin-2-yl Butyl Butyl  85-105°428.2 3 Pyridin-3-yl Butyl Butyl 224-229° 428.2 4 Pyrazin-2-yl ButylButyl   243° 429.2 5 [1,2,4]Triazolo[1,5-α]pyridin-6-yl Butyl Butyl n.d.468.2 6 2-Methyl-[1,2,4]triazolo[1,5-α]pyridin-6-yl Butyl Butyl n.d.482.3 7 Imidazo[1,2-α]-pyridin-6-yl Butyl Butyl 262.5° 467.3 82-Methyl-imidazo[1,2-α]pyridin-6-yl Butyl Butyl 254-257° 481.3 9Pyridin-4-yl Ethoxymethyl Ethoxymethyl   132° 432.1 10 PhenylEthoxymethyl Ethoxymethyl  92-95° 431 11 Phenyl CyclopropylmethylCyclopropylmethyl  84-89° 423 12 Pyridin-4-yl CyclopropylmethylCyclopropylmethyl 146-149 424 13 Phenyl1-(2-Cyclohexyl-ethyl)-piperidin-4-yl 163-166° 494.7 14 Phenyl6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-yl  80-85° 445.5 15 PhenylTetrahydro-pyran-4-yl 183-186° 385.5 16 Phenyl3,3,5,5-Tetramethyl-cyclohexyl 101-106° 439.6 17 Phenyl Cyclooctyl 95-100° 411.5 18 6-Methoxy-pyridin-3-yl Butyl Butyl 103-108° 458.6 191-Methyl-6-oxo-1,6-dihydro-pyridin-3-yl Butyl Butyl 175-180° 574.7 202-Methoxy-pyridin-4-yl Butyl Butyl 162-165° 458.6 212-Phenyl-thiazol-4-yl Butyl Butyl  95-100° 510.7 22Benzo[1,2,5]thiadiazol-5-yl Ethoxymethyl Ethoxymethyl  90-95° 489.6 23Quinoxalin-6-yl Ethoxymethyl Ethoxymethyl 110-116° 483.6 241-Methyl-6-oxo-1,6-dihydro-pyridin-3-yl Ethoxymethyl Ethoxymethyl132-137° 462.5

1. A compound of formula I

wherein R₁ is a group of formula

 wherein R₆ is (C₁₋₄)alkyl, R₇ and R₈, independently, are hydrogen or(C₁₋₄)alkyl and X is hydrogen, (C₁₋₄)alkoxy, (C₁₋₄)alkylamino ordi(C₁₋₄)alkylamino, R₂ and R₃, independently, are(C₁₋₄)alkoxy(C₁₋₄)alkyl or (C₃₋₇)cycloalkyl(C₁₋₄)alkyl, or, provided R₁is not an optionally substituted phenyl group, (C₁₋₁₂)alkyl, R₄ ishydrogen, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen or trifluoromethyl and R₅is hydrogen or (C₁₋₄)alkyl, in free base or acid addition salt form. 2.The compound according to claim 1 which is(R)-1,1-bis-ethoxymethyl-3-(4-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline,in free base or acid addition salt form.
 3. A process for thepreparation of a compound of formula I as defined in claim 1, or a saltthereof, which comprises reacting a compound of formula II

wherein R₁, R₄ and R₅ are as defined in claim 1, with a compound offormula III

wherein R₂ and R₃ are as defined in claim 1, and recovering theresulting compound of formula I in free base or acid addition salt form.4. A pharmaceutical composition comprising a compound of claim 1 in freebase of pharmaceutically acceptable acid addition salt form, inassociation with a pharmaceutical carrier or diluent.
 5. A combinationcomprising a therapeutically effective amount of a compound of claim 1in free base or pharmaceutically acceptable acid addition salt form anda second drug substance, for simultaneous or sequential administration.6. A method for the treatment of depression, anxiety and bipolardisorders in a subject in need of such treatment, which comprisesadministering to such subject a therapeutically effective amount of acompound of claim 1 in free base or pharmaceutically acceptable acidaddition salt form.